Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic fibrosis adults homozygous for F508DEL-CFTR

J Cyst Fibros. 2017 May;16(3):371-379. doi: 10.1016/j.jcf.2017.01.009. Epub 2017 Feb 13.

Abstract

Background: Cavosonstat (N91115), an orally bioavailable inhibitor of S-nitrosoglutathione reductase, promotes cystic fibrosis transmembrane conductance regulator (CFTR) maturation and plasma membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators.

Methods: A Phase I program evaluated pharmacokinetics, drug-drug interactions and safety of cavosonstat in healthy and cystic fibrosis (CF) subjects homozygous for F508del-CFTR. Exploratory outcomes included changes in sweat chloride in CF subjects.

Results: Cavosonstat was rapidly absorbed and demonstrated linear and predictable pharmacokinetics. Exposure was unaffected by a high-fat meal or rifampin-mediated effects on drug metabolism and transport. Cavosonstat was well tolerated, with no dose-limiting toxicities or significant safety findings. At the highest dose, significant reductions from baseline in sweat chloride were observed (-4.1mmol/L; P=0.032) at day 28.

Conclusions: The favorable safety and clinical profile warrant further study of cavosonstat in CF. ClinicalTrials.gov Numbers: NCT02275936, NCT02013388, NCT02500667.

Keywords: CFTR stabilizer; Cystic fibrosis; GSNOR, F508del-CFTR; Homozygous; Modulator.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aldehyde Oxidoreductases / antagonists & inhibitors*
  • Aminophenols / pharmacology*
  • Aminopyridines / pharmacology*
  • Benzodioxoles / pharmacology*
  • Biological Availability
  • Biphenyl Compounds / administration & dosage
  • Biphenyl Compounds / adverse effects
  • Biphenyl Compounds / pharmacokinetics
  • Biphenyl Compounds / pharmacology
  • Cystic Fibrosis Transmembrane Conductance Regulator* / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator* / metabolism
  • Cystic Fibrosis* / drug therapy
  • Cystic Fibrosis* / genetics
  • Cystic Fibrosis* / metabolism
  • Cytochrome P-450 CYP3A Inducers / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Drug Interactions
  • Drug Monitoring / methods
  • Female
  • Humans
  • Male
  • Membrane Transport Modulators / pharmacology*
  • Mutation
  • Pharmacogenetics
  • Quinolones / pharmacology*
  • Rifampin / pharmacology*
  • Treatment Outcome

Substances

  • Aminophenols
  • Aminopyridines
  • Benzodioxoles
  • Biphenyl Compounds
  • Cytochrome P-450 CYP3A Inducers
  • Drug Combinations
  • Membrane Transport Modulators
  • Quinolones
  • cavosonstat
  • lumacaftor, ivacaftor drug combination
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Aldehyde Oxidoreductases
  • formaldehyde dehydrogenase, glutathione-independent
  • Rifampin

Associated data

  • ClinicalTrials.gov/NCT02275936
  • ClinicalTrials.gov/NCT02013388
  • ClinicalTrials.gov/NCT02500667